Oxidative stress sensitizes bladder cancer cells to TRAIL mediated apoptosis by down-regulating anti-apoptotic proteins.
Oxidative stress sensitizes bladder cancer cells to TRAIL mediated apoptosis by down-regulating anti-apoptotic proteins.
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DOI：
10.1016/j.juro.2009.05.005
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Voelkel-Johnson C
中科院分区：
文献类型：
--
作者：
White-Gilbertson SJ;Kasman L;McKillop J;Tirodkar T;Lu P;Voelkel-Johnson C
TRAIL是一种参与免疫监视的内源性蛋白质，也是临床试验中的一种新药，作为癌症治疗剂特别令人感兴趣，因为它可以诱导癌细胞而不是正常细胞的凋亡。由于一些癌症对TRAIL产生抗性，安全有效的TRAIL致敏方法具有很大的临床意义。这项研究探讨了化疗和氧化应激如何影响肿瘤坏死因子相关凋亡配体的敏感性和细胞凋亡途径中蛋白质的表达。在活力测定中评估对TRAIL的敏感性。凋亡通过半胱天冬酶-3/7活性和/或使用Hoechst染色的核凝聚来测量。蛋白质印迹法用于确定蛋白质表达的切割、磷酸化或改变。TRAIL可降低5637膀胱癌细胞的存活率，但对J82和T24膀胱癌细胞无影响。多柔比星或顺铂化疗降低了抗凋亡蛋白cFLIPS的表达，增加了caspase-8的裂解，逆转了T24细胞的TRAIL耐药性。通过siRNA特异性靶向cFLIPS不足以在T24细胞中对TRAIL致敏。然而，化疗介导的TRAIL致敏作用被低浓度的过氧化氢模拟，这导致翻译延伸因子2（EF 2）的磷酸化和几种短半衰期的抗凋亡蛋白（包括FLIPS、XIAP和存活素）的表达减少。低浓度过氧化氢诱导的氧化应激可能会逆转肿瘤坏死因子相关凋亡配体（TRAIL）的耐药性，因此需要进一步探索过氧化氢作为膀胱内辅助治疗以降低膀胱癌细胞的凋亡阈值。
TRAIL, an endogenous protein involved in immunosurveillance and a novel drug in clinical trials, is of particular interest as a cancer therapeutic because it can induce apoptosis in cancer cells but not in normal cells. Since some cancers develop resistance to TRAIL, safe and effective methods of TRAIL sensitization are of great clinical interest. This study explores how chemotherapy and oxidative stress affect TRAIL sensitivity and expression of proteins in the apoptotic pathway. Sensitivity to TRAIL was assessed in viability assays. Apoptosis was measured by caspase-3/7 activity and/or nuclear condensation using Hoechst staining. Western blotting was used to determine cleavage, phosphorylation, or alterations in protein expression. TRAIL reduced the viability of 5637 but not J82 and T24 bladder carcinoma cells. Chemotherapy with doxorubicin or cisplatin decreased the expression of the anti-apoptotic protein cFLIPS and increased caspase-8 cleavage, reversing TRAIL resistance in T24 cells. Specific targeting of cFLIPS by siRNA was insufficient for sensitization to TRAIL in T24 cells. However, chemotherapy-mediated TRAIL sensitization was mimicked by low concentrations of hydrogen peroxide, which resulted in phosphorylation of translation elongation factor 2 (EF2) and reduced expression of several short half-life, anti-apoptotic proteins including FLIPS, XIAP, and survivin. Induction of oxidative stress by low concentrations of hydrogen peroxide may reverse TRAIL resistance and warrants the further exploration of hydrogen peroxide as an adjuvant intravesical treatment to lower the apoptotic threshold of bladder cancer cells.
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影响因子：
6.6
作者：
Herr, Harry W.;Moralest, Alvaro
通讯作者：
Moralest, Alvaro
影响因子：
7.4
作者：
White, Shai J.;Kasman, Laura M.;Voelkel-Johnson, Christina
通讯作者：
Voelkel-Johnson, Christina
DOI：
10.1016/j.urolonc.2007.11.031
发表时间：
2008-07-01
影响因子：
2.7
作者：
Simons, Mark P.;O'Donnell, Michael A.;Griffith, Thomas S.
通讯作者：
Griffith, Thomas S.
影响因子：
3.6
作者：
White, Shai J.;Lu, Ping;Voelkel-Johnson, Christina
通讯作者：
Voelkel-Johnson, Christina
氧化还原状态的改变伴随着人类转移性膀胱癌的进展。
影响因子：
7.4
作者：
Hempel, Nadine;Ye, Hanqing;Abessi, Bryan;Mian, Badar;Melendez, J. Andres
通讯作者：
Melendez, J. Andres